The invention relates to a method and a device for the non-invasive detection or determination, by Raman spectroscopy, of the concentration of substances in body fluids. In particular the invention is concerned with detection or determination of concentrations of glucose, cholesterol, lactate or such in human blood.
For the detection of substances dissolved in the blood of a patient in most cases a blood sample is taken from the patient and subsequently analysed. Provided this blood sample is taken as outpatient only once or in relatively large intervals and by skilled personnel this is not an excessive inconvenience for the patient. However, if a frequent, recurring investigation of the blood is required in regular intervals as for diabetes patients, a frequent taking of blood samples of the patient in a hospital or in a GP surgery constitutes an excessive inconvenience. For this reason so called “home monitoring” procedures have been developed by which the patient can control himself, independent of when and where. However, this implies that the patient always carries the required instrument with himself. The general disadvantage of these procedures is that the taking of a blood sample in each event carries an infection risk—albeit a very small one. If the required instruments (syringes etc.) are not sterile or not available as sterile a blood investigation is not possible. Even bigger difficulties arise from blood analysis by taking of a blood sample for patients disposed with haemophilia. In each case the blood analysis by taking of a blood sample implies a more or less painful operation and an effort the patient is not always up to.
The blood sample taken in a hospital or a GP's surgery must be analysed in a laboratory by (wet) chemical methods. In the case of the “home monitoring” methods the patient uses dry chemical equipment (minilab), frequently in the form of test strips often integrating the blood sample taking in one instrument together, so the analysis in a specially equipped laboratory is no longer required. The disadvantage of any chemical analysis, however, remains in the very high standards that must be demanded for cleanliness and precision of dosage. In addition, for all in vitro methods, there persists the danger that blood and/or chemicals are released into the environment and with that pathogens can be distributed under circumstances.
The taking of a blood sample, often several times per day, constitutes a big burden for the patient both in terms of his health and psychological condition as well as by the restriction of his mobility.
For this reason methods have been developed that permit an investigation of the blood of a patient in vivo without taking a blood sample and that allow the giving of a result without any significant time delay inevitable for a chemical analysis. In, particular, procedures have been described for the determination of the concentration of medically relevant substances in a patient's body, which are based on the changed physical properties of light by the substances to be detected.
From DE-A-195 18 511 a method is known for the transcutaneous determination of concentrations of substances in human blood without blood sampling. In case of this transcutaneous in vivo determination of concentration of substances in the patient's blood such as glucose, lactate, cholesterol, alcohol, drugs or such, a signal is measured by spectroscopic methods that corresponds to the amount of substance and to the amount of water in a given body region. The substance concentration in water is then determined by obtaining the ratio of the signal value for the substance and for the water from which the value for the concentration in blood of the substance is computed. In particular nuclear spin resonance spectroscopy and, in a more general context next to other spectroscopic methods, also Raman spectroscopy is mentioned.
However, severe problems stand in the way of an application of Raman spectroscopy for concentration measurements of substances in tissue fluids. The intensity of Raman scattering is only small and generally several, orders of magnitude smaller than Rayleigh scattering. For human tissue, due to the inhomogeneous and opaque properties of the medium, the Rayleigh scattering (here combining all scattering processes that do not change the scattered wavelength including the scattering from particles) can even be ca. 10 orders of magnitude stronger than the Raman scattering. This strong Rayleigh scattering “blinds” known detection systems in the region of the wavelength shifted Raman scattering. Other than Rayleigh scattering, depending on the excitation wavelength, human tissue can also show unwanted fluorescence or other perturbing light emission hiding the Raman signals. An additional problem results from the spectral superposition of Raman signals of different other substances with the Raman signal of the substance to be detected. Due to the complex composition of the medium, interfering signals result which can be substantially higher than the measured signals for the substance to be detected.
From DE 691 21 589 T2 a non-invasive method as well as a device is known for measuring the concentration of glucose in the ocular aqueous humour by Raman spectroscopy.
From DE 195 38 372 A1 a method and a device is known for a non-invasive glucose measurement in the eye by Raman spectroscopy.
From DE 692 19 580 T2 the determination is known of the composition and the concentration of an arbitrary gas mixture in the respiratory pathways of a patient by Raman spectroscopy.